This invention was made with Government support under grant NIH-AI-40093 awarded by the National Institutes of Health. The Government has certain rights in this invention.
NKT cells constitute a unique subpopulation of T lymphocytes, which are highly conserved in both human and murine species. NKT cells express some NK-specific surface markers, such as the C-type lectin NKRP-1A, thereby sharing some properties with classical NK cells. NKT cells also express a semi-invariant T cell receptor, consisting in humans of an invariant Vα24JαQ rearrangement paired preferentially with a variable Vβ11 chain. In the mouse, NKT cells express an invariant Vα14Jα281 rearrangement paired with variable Vβ8, Vβ7, or Vβ2. In terms of co-receptor expression, invariant NKT cells belong either to the single positive CD4+ or the double negative CD4−CD8−TCRα/β+ subset of lymphocytes.
Although natural ligands of NKT cells have not yet been identified, these cells are activated when their TCR recognizes glycosylceramides derived from marine sponges, presented by CD1d. Although this class of α-glycosylated ceramides are not detectable in mammals, they may share critical structural features with natural CD1d-ligands, suggesting that NKT cells recognize antigens containing a hydrophobic (lipid) and a hydrophilic moiety.
The biological role of NKT cells is not well defined. In response to activation through their T cell receptor, NKT cells have been shown to secrete large amounts of both interferon-γ (IFN-γ) and interleukin-4 (IL-4) (see, for example, Hong et al. (1999) Immunol Rev. 169:131; and Singh et al. (1999) J Immunol 163:2373). After repeated activation, NKT cells become polarized cells that produce predominantly IL-4.
It has also been suggested that NKT cells serve an immunoregulatory function in the control of susceptibility to certain autoimmune diseases. For example, in some disease models, transfer of NKT cells to disease-susceptible recipients prevents the development of autoimmune disease, and it has been suggested that activation of NKT cells could provide for therapeutic intervention for the immunoregulation of autoimmune disease (Sharif et al. (2002) J. Mol. Med. 80:290-300) by polarizing conventional T cells toward IL-4 production. It has also been reported that NKT cells and IL-13 (possibly produced by NKT cells) can down-regulate cytotoxic T lymphocyte-mediated tumor immunosurveillance (Terabe et al. (2000) Nat Immunol 1(6):515-20).
However, it has also been reported that activation of NKT cells augments Th1-type immune responses and autoantibody secretion that contribute to lupus development in adult NZB/W mice (Zeng et al. (2003) J Clin Invest 112:1211).
The role of NKT cells in human clinical conditions is of great interest. There is a high level of conservation between species for the NKT cell system. α-Galactosylceramide can stimulate both murine and human NKT cells, and both mouse and human CD1d molecules are able to present α-GalCer to NKT cells from either species, indicating the relevance of animal studies for human clinical trials. Methods of manipulating NKT cell responses are provided by the present invention.